The antiproliferative and synergistic effects of immune interferon (IFN-Gamma) and the synthetic double-stranded RNA (dsRNA), poly(I).poly(C), on human colon carcinoma cell lines HT-29 and BE were examined in vitro. HT-29 cells which are sensitive to the cytocidal effects of IFN-Gamma show a synergistic antiproliferative response to IFN-Gamma and poly(I).poly(C), the latter of which is noncytotoxic. BE cells which are resistant to IFN-Gamma are sensitized in the presence of poly(I).poly(C). The synergistic effects of IFN-Gamma and poly(I).poly(C) were related to inhibition of transcription of rRNA in HT-29 cells but not in BE cells and were unrelated to the IFN-Gamma-mediated induction of 2',5'(oligo)adenylate synthetase in either cell line. In other studies, poly(I).poly(C) administered i.v. to mice bearing the L1210 leukemia transplanted s.c., produced an increase in the therapeutic index of 5-fluorouracil or 5-fluorouridine were administered i.v. and concurrently with poly(I).poly(C). These effects correlated with an increased IFN production and associated 2',5'(oligo)A synthetase activity in the bone marrow and spleen, implying a cytoprotective effect by endogeneously secreted IFN. Current studies are examining the synergism between poly(I).poly(C) and epidermal growth factor (EGF) in the dsRNA-sensitive cell line A431, a human epidermoid carcinoma containing an amplification in the EGF receptor gene. The proliferative response of a clone of A431 cells to EGF is being studied with respect to its response to EGF and poly(I).poly(C) and the activity of topoisomerase II and its associated tyrosine kinase activity.